Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. Unfortunately, current antipsychotics induce severe side effects and are ineffective in treating a number of the symptoms of schizophrenia. The development of more effective pharmacotherapies will likely await a better understanding of the neurobiology of schizophrenia. The present experiments will examine the contribution of a novel source of glutamate, specifically nonvesicular glutamate release from cystine-glutamate antiporters, to the behavioral and neurochemical effects of phencyclidine (PCP), which represents one of the most commonly used animal models of schizophrenia. The experiments in the first aim will test the hypothesis that targeting the cystine-glutamate antiporter using the cysteine prodrug N-acetylcysteine represents a novel treatment strategy for schizophrenia. Specifically, these experiments will examine the impact of N-acetylcysteine treatment on locomotor activity, deficits in working memory and social withdrawal) reduced by acute and subchronic administration of PCP. These behaviors have been used previously to gain insight into the neurobiology of schizophrenia. Additional experiments in this aim will utilize in vivo microdialysis to assess the capacity of N-acetylcysteine administration to reverse the neurochemical effects of PCP in the medial prefrontal cortex. The experiments in the second aim will test the hypothesis that a dysregulation in the activity of cystine-glutamate antiporters contributes to the pathophysiology of PCP, and potentially schizophrenia. Specifically these experiments will examine whether acute or repeated administration of PCP alters extracellular or tissue levels of cystine and glutathione in the medial prefrontal cortex. Collectively, these experiments have the potential to identify the cystine-glutamate antiporter as a novel cellular mechanism in the pathophysiology of schizophrenia, as well as to demonstrate the potential antipsychotic properties of N-acetylcysteine. [unreadable] [unreadable]